The unifying goal of this program project proposai is to define the principles governing normal nervous system development, and the manner in which failure of the normal developmental processes may lead to brain dysfunction and mental retardation. The studies for the most part are basic in nature, focussing on various aspects of the cell and its environment that are involved in overall development processes, including examination of the extracellular matrix (ECM) and possible external signals which provide the milieu for cell differentiation and proliferation. In Project I, the structure and function of proteoglycans (PG) and hyaluronate of the ECM will be examined in normal brain (compared with cartilage) and in a mouse mutant defective in PG synthesis, exhibiting (among other abnormalities) hydrocephalus. In Project II, the outgrowth of neurites on the ECM component, laminin, and its role in neural development will be examined. In Project Ill, the role of insulin and insulin-like growth factors in regulating growth and development of nervous system will be elucidated. Other studies will identify the structural gene defects in certain human genetic disorders and use this information to understand the resulting mental retardation. In Project IV, an inherited storage disease, beta-mannosidosis will be studied by cloning the gene for beta-mannosidase and using it in gene replacement studies in a goat model system. Traditionally a major focus of this program has been on genetic disorders that may have associated nervous system dysfunction and/or mental retardation. In the present proposal, these two highly relevant animal models, one involving a defect in the ability to degrade certain glycoconjugates, and the other involving a defect in the ability to synthesize a particular glycoconjugate should be amenable to genetic manipulations and may lead to therapeutic strategies for human disorders . A comprehensive multi-disciplinary approach using biochemical, pharmacologic, morphologic and cell culture techniques with expanding emphasis on molecular genetics approaches will be used in all four projects. The derivative information from these proposed studies should define specific loci where disease processes may intervene, leading to abnormal nervous system development and mental retardation.